Stable liquid preparation of a vitamin complex for internal use

Abstract: Described is a stable liquid preparation of complex vitamin for internal use. The preparation containing vitamin B₁ and vitamin B₁₂, and as a sweetening agent, a sugar alcohol. The pH of the preparation has been adjusted to 3.5 to 4.5.

Description: BACKGROUND OF THE INVENTION a) Field of the Invention This invention relates to a stable liquid preparation of complex vitamin for internal use, and more specifically to a liquid preparation of complex vitamin for internal use, which remains stable even when stored for a long period at room temperature. b) Description of the Related Art Like vitamin B 6 , vitamin B 1 and vitamin B 12 are closely associated with nervous functions and are effective for the improvement of neuroses such as neuralgia, arthralgia, peripheral neuritis and peripheral paralysis. A variety of tablets and capsules added with these vitamins are therefore available on the market. As a dosage form, a liquid preparation generally features that compared with such tablets and capsules, the liquid preparation is more readily absorbed in the body and is easier to take. Nonetheless, no stable liquid preparation added with both vitamin B 1 and vitamin B 12 has been available on the market. This is attributed to the poor storage stability of a liquid preparation containing both of them. As causes for the poor storage stability of the liquid preparation added with both vitamin B 1 and vitamin B 12 , it is known that the stable pH ranges of these vitamins in an aqueous solution are different, i.e., pH 2-4 for vitamin B 1 and pH 4.5-5 for vitamin B 12 and also that SH-containing decomposition products of vitamin B 1 extremely lower the stability of vitamin B 12 . Further, sucrose is generally used as a sweetening agent in liquid preparations for internal use. Sucrose may however lower the stability of vitamin B 1 and vitamin B 12 , depending on its concentration and the pH. Liquid preparations for internal use are also added with a corrigent, a flavoring agent, a buffer agent, a preservative and the like. These additives may also give adverse effects on the stability, thereby making it more difficult to formulate a liquid preparation for internal use, which contains vitamin B 1 and vitamin B 12 . JP 02240025 A2 describes the preparation of stable aqueous solutions containing vitamins B 1 and B 12 . The solutions further contain polydextrose as a stabilizer for the vitamins. SUMMARY OF THE INVENTION An object of the present invention is therefore to provide a liquid preparation for internal use, which contains vitamin B 1 and vitamin B 12 and remains stable even when stored for a long period at room temperature. With the foregoing circumstances in view, the present inventors have proceeded with extensive research. As a result, it has been found that the above-described problem can be overcome by the addition of vitamin B 1 and vitamin B 12 to a particular solution base, leading to the completion of the present invention. In one aspect of the present invention, there is thus provided a stable liquid preparation of complex vitamin for internal use, said preparation containing vitamin B 1 and vitamin B 12 , comprising a sugar alcohol as a sweetening agent, wherein the sugar alcohol is xylitol, maltitol or sorbitol, the pH of said preparation having been adjusted to 3.5 to 4.5. In the liquid preparation of complex vitamin for internal use according to the present invention, the activities of vitamin B 1 and vitamin B 12 are stably maintained without reduction even when the liquid preparation is stored for a long period at room temperature. DETAILED DESCRIPTION OF THE INVENTION AND PREFERRED EMBODIMENTS In the present invention, examples of vitamin B 1 include thiamine and thiamine derivatives such as fursultiamine, octotiamine, thiamine disulfide, bis-bentiamine, bisbutitiamine, bisibutiamine and benfotiamine as well as their salts. Their hydrochlorides, nitrates and the like can be mentioned as these salts. Vitamin B 1 can preferably be added in an amount of 1-50 mg per 50 mℓ of the liquid preparation of complex vitamin for internal use (hereinafter called "the present preparation"). On the other hand, cyanocobalamin is preferred as vitamin B 12 . It is preferred to add it in an amount of 1-5,000 µ g in the present preparation. The sugar alcohols used as sweetening agents in the present invention are xylitol, maltitol or sorbitol. Since these sugar alcohols have the merit that they are hardly digestible and do not raise the blood sugar level, they are advantageous particularly for those suffering from diabetes mellitus or obesity. The sugar alcohol can be added preferably in an amount of 0.5-20 g, notably 1-15 g in the present preparation. The above sugar alcohol has lower sweetness compared with sucrose, so that sucrose can be added to the liquid preparation of complex vitamin for internal use according to the present invention to supplement the sweetness. From the standpoint of stability of both the vitamins, it is necessary to limit the amount of added sucrose below 5 g in the present preparation. As a pH regulator for adjusting the pH to 3.5-4.5 in the present invention, it is preferred to use an organic acid such as citric acid, malic acid, tartaric acid or succinic acid or a salt thereof which can reduce the bitterness of added ingredients and can make the preparation easier to take, although hydrochloric acid, sodium hydroxide or the like may be used. Regarding the amount of such an organic acid or a salt thereof in the liquid preparation of complex vitamin for internal use, it is preferred to limit its amount to not greater than 0.5 g in the present preparation. In addition to the above-described essential ingredients, the liquid preparation of complex vitamin for internal use according to the present invention can be added, as needed, with optional ingredients, for example, drug efficacy ingredients such as B 2 vitamins, B 6 vitamins, E vitamins, nicotinic acid, nicotinamide, pantothenic acids, pantothenol, aminoethylsulfonic acid, anhydrous caffeine, γ-oryzanol, and crude drug ingredients, e.g., ginseng; solubilizers such as ethanol and polyoxyethylene-hydrogenated castor oil; preservatives such as benzoic acid and alkyl parabens (i.e., alkyl parahydroxybenzoates); coloring agents such as caramel; and perfumes. The present invention will hereinafter be described in further detail by the following Examples, Comparative Examples and Test. It should however be borne in mind that the present invention is not limited to them in any way whatsoever. Example 1 The ingredients indicated in Table 1 were-weighed in the amounts specified there and were then dissolved in purified water to give a total volume of 20 mℓ. The resulting solution was filtered through a 0.45- µ m membrane filter and filled in a 20-mℓ amber-colored glass bottle. The glass bottle was plugged and then subjected to sterilization at 80°C for 20 minutes, whereby a liquid preparation of complex vitamin for internal use was produced. Incidentally, thiamine nitrate and cyanocobalamin were added 115% on their indicated amounts. Thiamine nitrate 10 mg Cyanocobalamin 1,500 µg Pyridoxine hydrochloride 100 mg Nicotinamide 50 mg Pantothenol 30 mg D-Sorbitol solution (70%) 2,000 mg Xylitol 2,500 mg Malic acid 20 mg Sodium hydroxide Sufficient to adjust the pH to 4.0 Sodium benzoate 14 mg Butyl parahydroxybenzoate 1 mg Caramel 100 mg Perfume trace Purified water Sufficient to produce 20 mℓ Example 2 Following the procedures of Example 1, a liquid preparation of complex vitamin for internal use was produced in accordance with the formulation shown in Table 2. Thiamine nitrate 10 mg Cyanocobalamin 1,500 µg Pyridoxine hydrochloride 50 mg Nicotinamide 60 mg Pantothenol 15 mg D-Sorbitol solution (70%) 3,000 mg Maltitol solution (75%) 4,000 mg Citric acid 80 mg Sodium citrate Sufficient to adjust the pH to 4.0 (15 mg) Sodium benzoate 35 mg Butyl parahydroxybenzoate 4 mg Caramel 50 mg Perfume trace Purified water Sufficient to produce 50 mℓ Example 3 Following the procedures of Example 1, a liquid preparation of complex vitamin for internal use was produced in accordance with the formulation shown in Table 3. Fursultiamine hydrochloride 6 mg Cyanocobalamin 1,500 µg Pyridoxine hydrochloride 10 mg Riboflavin sodium phosphate 5 mg Nicotinamide 25 mg Anhydrous caffeine 50 mg Aminoethylsulfonic acid 1,000 mg D-Sorbitol solution (70%) 7,000 mg Purified sucrose 4,000 mg Citric acid 200 mg Sodium citrate Sufficient to adjust the pH to 3.7 (120 mg) Sodium benzoate 35 mg Butyl parahydroxybenzoate 4 mg Caramel 5 mg Perfume trace Purified water Sufficient to produce 50 mℓ Example 4 Following the procedures of Example 1, a liquid preparation of complex vitamin for internal use was produced in accordance with the formulation shown in Table 4. Fursultiamine hydrochloride 6 mg Cyanocobalamin 1,500 µg Pyridoxine hydrochloride 10 mg Nicotinamide 50 mg Anhydrous caffeine 50 mg Liquid ginseng extract 0.6 mℓ Liquid polygonati rhizoma extract 0.4 mℓ Liquid cistanchis herba extract 0.3 mℓ D-Sorbitol solution (70%) 5,000 mg Xylitol 1,500 mg Purified sucrose 2,000 mg Citric acid Sufficient to adjust the pH to 4.2 (100 mg) Sodium citrate 120 mg Polyoxyethylene-hydrogenated castor oil 60 10 mg Sodium benzoate 35 mg Butyl parahydroxybenzoate 4 mg Caramel 5 mg Perfume trace Purified water Sufficient to produce 50 mℓ Comparative Example 1 Following the procedures of Example 1, a liquid preparation of complex vitamin for internal use was produced in accordance with the formulation shown in Table 5. Thiamine nitrate 10 mg Cyanocobalamin 1,500 µg Pyridoxine hydrochloride 50 mg Nicotinamide 60 mg Pantothenol 15 mg Purified sucrose 2,000 mg Isomerized sugar 6,500 mg Citric acid 80 mg Sodium citrate Sufficient to adjust the pH to 4.0 Sodium benzoate 35 mg Butyl parahydroxybenzoate 4 mg Caramel 50 mg Perfume trace Purified water Sufficient to produce 50 mℓ Comparative Example 2 Following the procedures of Example 1, a liquid preparation of complex vitamin for internal use was produced in accordance with the formulation shown in Table 6. Thiamine nitrate 10 mg Cyanocobalamin 1,500 µg Pyridoxine hydrochloride 50 mg Nicotinamide 60 mg Pantothenol 15 mg Purified sucrose 7,500 mg Citric acid 250 mg Sodium citrate Sufficient to adjust the pH to 5.0 Sodium benzoate 35 mg Butyl parahydroxybenzoate 4 mg Caramel 50 mg Perfume trace Purified water Sufficient to produce 50 mℓ Test The liquid preparations of complex vitamin for internal use, which had been produced in Examples 1-4 and Comparative Examples 1-2, respectively, were stored at room temperature for 12 months and 24 months, followed by quantitative analyses of vitamin B 1 and vitamin B 12 . The results of the stability test of vitamin B 1 are shown in Table 7, whereas the results of the stability test of vitamin B 12 are presented in Table 8. The quantitative analyses were conducted by high performance liquid chromatography, and the stability of each liquid preparation is indicated by a value (%) on the indicated amount. Measurement of Stability of Vitamin B 1 After stored for 12 months After stored for 24 months Example 1 107.7 100.7 Example 2 108.8 100.8 Example 3 110.9 104.1 Example 4 109.6 102.7 Comp.Ex. 1 104.5 95.2 Comp.Ex. 2 96.3 78.9 At the time of production: 115.0% Measurement of Stability of Vitamin B 12 After stored for 12 months After stored for 24 months Example 1 104.2 93.7 Example 2 105.8 96.0 Example 3 107.0 99.0 Example 4 109.6 102.0 Comp.Ex. 1 99.5 83.0 Comp.Ex. 2 101.0 88.7 At the time of production: 115.0% Results As is evident from Table 7 and Table 8, vitamin B 1 and vitamin B 12 in each liquid preparation of complex vitamin for internal use according to this invention retained high stability.

Claims: A stable liquid preparation of complex vitamin for internal use, said preparation containing vitamin B 1 and vitamin B 12 comprising a sugar alcohol as a sweetening agent, whereby said sugar alcohol is xylitol, maltitol or sorbitol, and the pH of said preparation having been adjusted to 3.5 to 4.5. The preparation according to claim 1, wherein citric, malic, tartaric or succinic acid or a salt thereof has been used as a pH regulator in an amount not greater than 0.5 g per 50 ml of liquid preparation. The preparation according to claim 1, wherein vitamin B 1 is thiamine or a derivative thereof or a salt of thiamine or the thiamine derivative; and vitamin B 12 is cyanocobalamin. The preparation according to claim 3, wherein citric, malic, tartaric or succinic acid or a salt thereof has been used as a pH regulator in an amount not greater than 0.5 g per 50 ml of liquid preparation.

Inventors: AOKI NORIKO, IWASA AKIRA, KIKUCHI YUKO, KURAZUMI TOSHIAKI, MURATA TEIJI, MURATA YUTAKA, OHSUGI TOMOHIKO, AOKI, NORIKO, IWASA, AKIRA, KIKUCHI, YUKO, KURAZUMI, TOSHIAKI, MURATA, TEIJI, MURATA, YUTAKA, OHSUGI, TOMOHIKO
Applicants: SS PHARMACEUTICAL CO, SS PHARMACEUTICAL CO., LTD.
Application year: 1994
Main classification: A61K9
IPC codes: A61K47, A61K31, A61K9